Publications by authors named "Waldo H Belloso"

36 Publications

Clostridioides difficile infection in solid organ and hematopoietic stem cell transplant recipients: A prospective multinational study.

Transpl Infect Dis 2022 Feb 13;24(1):e13770. Epub 2021 Dec 13.

Saint Louis Hospital, Assistance Publique des ôpitaux de Paris Paris Diderot University, Sorbonne Paris Cite, Paris, France.

Background: Clostridioides difficile infection (CDI) is a significant cause of morbidity and mortality in recipients of solid organ transplant (SOT) or hematopoietic stem cell transplant (HSCT). In retrospective single center analyses, severe disease and relapse are common. We undertook an international, prospective cohort study to estimate the response to physician determined antibiotic treatment for CDI in patients with SOT and HSCT.

Methods: Adults with a first episode of CDI within the first 2 years of SOT or HSCT were enrolled. Demographics, comorbidities, and medication history were collected, and over 90 days of follow-up clinical cure, recurrences, and complications were assessed. Logistic regression was used to study associations of baseline predictors of clinical cure and recurrence. Odds ratios (ORs) and 95% confidence intervals (CIs) are cited.

Results: A total of 132 patients, 81 SOT and 51 HSCT (32 allogeneic), were enrolled with a median age of 56 years; 82 (62%) were males and 128 (97%) were hospitalized at enrollment. One hundred and six (80.3%) were diagnosed by DNA assay. CDI occurred at a median of 20 days post-transplant (interquartile range, IQR: 6-133). One hundred and eight patients (81.8%) were on proton pump inhibitors; 126 patients (95.5%) received antibiotics within the 6 weeks before CDI. The most common initial CDI treatments prescribed, on or shortly before enrollment, were oral vancomycin alone (50%) and metronidazole alone (36%). Eighty-three percent (95% CI: 76, 89) of patients had clinical cure; 18% (95% CI: 12, 27) of patients had recurrent CDI; global clinical cure occurred in 65.2%. Of the 11 patients who died, two (1.5% of total) were related to CDI. In multivariable logistic regression analyses, the type of initial treatment was associated with clinical cure (p = .009) and recurrence (p = .014). A history of cytomegalovirus (CMV) after transplant was associated with increased risk of recurrence (44% with versus 13% without CMV history; OR: 5.7, 95% CI: 1.5, 21.3; p = .01).

Conclusions: Among adults who develop CDI after SOT or HSCT, despite their immunosuppressed state, the percentage with clinical cure was high and the percentage with recurrence was low. Clinical cure and recurrence varied by type of initial treatment, and CMV viremia/disease was associated with an increased risk of recurrence.
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http://dx.doi.org/10.1111/tid.13770DOI Listing
February 2022

RBD-specific polyclonal F(ab´) fragments of equine antibodies in patients with moderate to severe COVID-19 disease: A randomized, multicenter, double-blind, placebo-controlled, adaptive phase 2/3 clinical trial.

EClinicalMedicine 2021 Apr 11;34:100843. Epub 2021 Apr 11.

mAbxience, Manuel Pombo Angulo 28, 3rd floor, Madrid 28050, Spain.

Background: passive immunotherapy is a therapeutic alternative for patients with COVID-19. Equine polyclonal antibodies (EpAbs) could represent a source of scalable neutralizing antibodies against SARS-CoV-2.

Methods: we conducted a double-blind, randomized, placebo-controlled trial to assess efficacy and safety of EpAbs (INM005) in hospitalized adult patients with moderate and severe COVID-19 pneumonia in 19 hospitals of Argentina. Primary endpoint was improvement in at least two categories in WHO ordinal clinical scale at day 28 or hospital discharge (ClinicalTrials.gov number NCT04494984).

Findings: between August 1st and October 26th, 2020, a total of 245 patients were enrolled. Enrolled patients were assigned to receive two blinded doses of INM005 ( = 118) or placebo ( = 123). Median age was 54 years old, 65•1% were male and 61% had moderate disease at baseline. Median time from symptoms onset to study treatment was 6 days (interquartile range 5 to 8). No statistically significant difference was noted between study groups on primary endpoint (risk difference [95% IC]: 5•28% [-3•95; 14•50];  = 0•15). Rate of improvement in at least two categories was statistically significantly higher for INM005 at days 14 and 21 of follow-up. Time to improvement in two ordinal categories or hospital discharge was 14•2 (± 0•7) days in the INM005 group and 16•3 (± 0•7) days in the placebo group, hazard ratio 1•31 (95% CI 1•0 to 1•74). Subgroup analyses showed a beneficial effect of INM005 over severe patients and in those with negative baseline antibodies. Overall mortality was 6•9% the INM005 group and 11•4% in the placebo group (risk difference [95% IC]: 0•57 [0•24 to 1•37]). Adverse events of special interest were mild or moderate; no anaphylaxis was reported.

Interpretation: Albeit not having reached the primary endpoint, we found clinical improvement of hospitalized patients with SARS-CoV-2 pneumonia, particularly those with severe disease.
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http://dx.doi.org/10.1016/j.eclinm.2021.100843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037439PMC
April 2021

A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia.

N Engl J Med 2021 02 24;384(7):619-629. Epub 2020 Nov 24.

From the Clinical Pharmacology Section (V.A.S., P.S., M.V.B., N.S.), Intermediate Care Unit (M.G.V., C.V., H.G.M.), and Infectious Diseases Section (M.L.S.), Department of Internal Medicine, and the Departments of Research (V.A.S., D.H.G., L.G.P., W.H.B.) and Transfusional Medicine (L.D.B.P., D.M.S., P.J.C., S.A.), Hospital Italiano de Buenos Aires, Buenos Aires; Department of Virology, Leloir Institute Foundation, Buenos Aires (A.V.G., D.S.O.), the Departments of Transfusional Medicine (K.R.), Infectious Diseases, Sanatorio Agote (G.P.V.), and Critical Care, Clínica Zabala (E.A.M.), Swiss Medical, Buenos Aires, the Departments of Infection Control (W.C.) and Transfusional Medicine (O.A.T.), Hospital Universitario Austral, Pilar, the Departments of Internal Medicine (F.M.R.) and Transfusional Medicine (M.S.), Clínica Santa Isabel, Buenos Aires, the Departments of Emergency and Internal Medicine (L.D.B.P., G.F.) and Transfusional Medicine (W.E.S.), Hospital Italiano Agustín Rocca, San Justo, the Departments of Medicine (M.H.L.) and Transfusional Medicine (I.F.), Hospital General de Agudos José María Ramos Mejía, Buenos Aires, the Departments of Internal Medicine (P.E.P.) and Transfusional Medicine (E.R.), Sanatorio Trinidad de Palermo, Buenos Aires, the Departments of Clinical Research (N.A.F., M.E.) and Transfusional Medicine (G.A.S.), Hospital Privado de la Comunidad de Mar del Plata and Escuela Superior de Medicina Universidad Nacional de Mar del Plata, Mar del Plata (N.A.F., M.E.), the Departments of Internal Medicine (P.R.) and Transfusional Medicine (J.P.), Hospital Zonal Ramón Carrillo, Bariloche, and the Departments of Infectious Diseases (E.C.N.) and Transfusional Medicine (A.M.), Sanatorio Británico de Rosario, Santa Fé - all in Argentina; and the Biostatistics Research Branch (D.F.), Division of Clinical Research (D.F., H.C.L.), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.

Background: Convalescent plasma is frequently administered to patients with Covid-19 and has been reported, largely on the basis of observational data, to improve clinical outcomes. Minimal data are available from adequately powered randomized, controlled trials.

Methods: We randomly assigned hospitalized adult patients with severe Covid-19 pneumonia in a 2:1 ratio to receive convalescent plasma or placebo. The primary outcome was the patient's clinical status 30 days after the intervention, as measured on a six-point ordinal scale ranging from total recovery to death.

Results: A total of 228 patients were assigned to receive convalescent plasma and 105 to receive placebo. The median time from the onset of symptoms to enrollment in the trial was 8 days (interquartile range, 5 to 10), and hypoxemia was the most frequent severity criterion for enrollment. The infused convalescent plasma had a median titer of 1:3200 of total SARS-CoV-2 antibodies (interquartile range, 1:800 to 1:3200). No patients were lost to follow-up. At day 30 day, no significant difference was noted between the convalescent plasma group and the placebo group in the distribution of clinical outcomes according to the ordinal scale (odds ratio, 0.83; 95% confidence interval [CI], 0.52 to 1.35; P = 0.46). Overall mortality was 10.96% in the convalescent plasma group and 11.43% in the placebo group, for a risk difference of -0.46 percentage points (95% CI, -7.8 to 6.8). Total SARS-CoV-2 antibody titers tended to be higher in the convalescent plasma group at day 2 after the intervention. Adverse events and serious adverse events were similar in the two groups.

Conclusions: No significant differences were observed in clinical status or overall mortality between patients treated with convalescent plasma and those who received placebo. (PlasmAr ClinicalTrials.gov number, NCT04383535.).
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http://dx.doi.org/10.1056/NEJMoa2031304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722692PMC
February 2021

On Innovation.

Authors:
Waldo H Belloso

Ther Innov Regul Sci 2020 09 5;54(5):1068-1075. Epub 2020 Feb 5.

National Administration of Drugs, Food and Medical Technology, Buenos Aires, Argentina.

Innovation has become an increasingly common topic in healthcare. Private companies, developers, payers, and regulators are devoting attention toward innovative products and processes as a crucial component of their interests in and occupation with healthcare services. Even when there is no consensus as to its definition, "innovation" -as opposed to "invention"- is broadly understood to refer turning a good idea into a practical solution. Adoption and applicability are key components of implementation that are sustained not only on innovation's attributes themselves but also in the characteristics of providers, users, and implementing organizations, as well as the external environment. Regulatory agencies often face the need to make decisions about proposed innovations with obsolete or inadequate normative frameworks and with a high degree of uncertainty about its eventual performance or its risks. Early interaction between developers and dedicated multidisciplinary teams at regulatory agencies may prove instrumental for speeding up the time required for proper evaluation and product registration, as well as the establishment of quality validation mechanisms. Community involvement both in the adoption and vigilance on innovative products and processes is crucial for completing the process of defining their roles and uses.
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http://dx.doi.org/10.1007/s43441-020-00125-3DOI Listing
September 2020

A randomized evaluation of on-site monitoring nested in a multinational randomized trial.

Clin Trials 2020 02 24;17(1):3-14. Epub 2019 Oct 24.

National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Background: Evidence from prospectively designed studies to guide on-site monitoring practices for randomized trials is limited. A cluster randomized study, nested within the Strategic Timing of AntiRetroviral Treatment (START) trial, was conducted to evaluate on-site monitoring.

Methods: Sites were randomized to either annual on-site monitoring or no on-site monitoring. All sites were centrally monitored, and local monitoring was carried out twice each year. Randomization was stratified by country and projected enrollment in START. The primary outcome was a participant-level composite outcome including components for eligibility errors, consent violations, use of antiretroviral treatment not recommended by protocol, late reporting of START primary and secondary clinical endpoints (defined as the event being reported more than 6 months from occurrence), and data alteration and fraud. Logistic regression fixed effect hierarchical models were used to compare on-site versus no on-site monitoring for the primary composite outcome and its components. Odds ratios and 95% confidence intervals comparing on-site monitoring versus no on-site monitoring are cited.

Results: In total, 99 sites (2107 participants) were randomized to receive annual on-site monitoring and 97 sites (2264 participants) were randomized to be monitored only centrally and locally. The two monitoring groups were well balanced at entry. In the on-site monitoring group, 469 annual on-site monitoring visits were conducted, and 134 participants (6.4%) in 56 of 99 sites (57%) had a primary monitoring outcome. In the no on-site monitoring group, 85 participants (3.8%) in 34 of 97 sites (35%) had a primary monitoring outcome (odds ratio = 1.7; 95% confidence interval: 1.1-2.7; p = 0.03). Informed consent violations accounted for most outcomes in each group (56 vs 41 participants). The largest odds ratio was for eligibility violations (odds ratio = 12.2; 95% confidence interval: 1.8-85.2; p = 0.01). The number of participants with a late START primary endpoint was similar for each monitoring group (23 vs 16 participants). Late START grade 4 and unscheduled hospitalization events were found for 34 participants in the on-site monitoring group and 19 participants in the no on-site monitoring group (odds ratio = 2.0; 95% confidence interval: 1.1-3.7; p = 0.02). There were no cases of data alteration or fraud. Based on the travel budget for on-site monitoring and the hours spent conducting on-site monitoring, the estimated cost of on-site monitoring was over US$2 million.

Conclusion: On-site monitoring led to the identification of more eligibility and consent violations and START clinical events being reported more than 6 months from occurrence as compared to no on-site monitoring. Considering the nature of the excess monitoring outcomes identified at sites receiving on-site monitoring, as well as the cost of on-site monitoring, the value to the START study was limited.
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http://dx.doi.org/10.1177/1740774519881616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992467PMC
February 2020

ART in HIV-Positive Persons With Low Pretreatment Viremia: Results From the START Trial.

J Acquir Immune Defic Syndr 2019 08;81(4):456-462

Faculty of Medicine, Kirby Institute, University of New South Wales, Sydney, Australia.

Background: The benefit of immediate antiretroviral therapy (ART) at CD4 >500 cells/μL was established in the Strategic Timing of Antiretroviral Treatment (START) study. The benefits and risks of immediate ART in participants with low pretreatment viremia, including virologic suppressors, were further assessed.

Setting: Randomized prospective international study.

Methods: START participants with enrollment viremia <3000 c/mL were included. We compared clinical outcomes (grade 4 adverse events, hospitalizations, or death), plasma viremia, CD4 counts, and changes in biomarkers in immediate versus deferred ART groups.

Results: Participants (N = 1134 including 93 with viremia ≤50 c/mL) had a median age of 37 years, 40% were women, and median CD4 was 713 cells/µL. Ninety-seven percent in the immediate and 29% in the deferred arm initiated ART at a median of 6 and 699 days, respectively. Clinical outcomes were experienced in 64 versus 61 patients in immediate and deferred arms (hazard ratio 1.10, 95% confidence interval: 0.77 to 1.56). The CD4 count difference was 125 cells/µL at 12 and 235 cells/µL at 36 months higher in the immediate versus deferred groups. D-dimer and VCAM levels decreased, and C-reactive protein increased, in the immediate arm at month 8. No significant changes in CD4 counts or biomarkers were observed in persons who maintained spontaneous virologic suppression.

Conclusions: START participants with low enrollment viremia experienced higher CD4 counts, greater proportion with suppressed viremia, and decreases in D-dimer levels on immediate ART despite the lack of difference in serious clinical outcomes. These data support immediate ART in people with low viremia, although equipoise remains for suppressors.
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http://dx.doi.org/10.1097/QAI.0000000000002052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6607914PMC
August 2019

Artificial Pancreas: Clinical Study in Latin America Without Premeal Insulin Boluses.

J Diabetes Sci Technol 2018 09 12;12(5):914-925. Epub 2018 Jul 12.

7 Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.

Background: Emerging therapies such as closed-loop (CL) glucose control, also known as artificial pancreas (AP) systems, have shown significant improvement in type 1 diabetes mellitus (T1DM) management. However, demanding patient intervention is still required, particularly at meal times. To reduce treatment burden, the automatic regulation of glucose (ARG) algorithm mitigates postprandial glucose excursions without feedforward insulin boluses. This work assesses feasibility of this new strategy in a clinical trial.

Methods: A 36-hour pilot study was performed on five T1DM subjects to validate the ARG algorithm. Subjects wore a subcutaneous continuous glucose monitor (CGM) and an insulin pump. Insulin delivery was solely commanded by the ARG algorithm, without premeal insulin boluses. This was the first clinical trial in Latin America to validate an AP controller.

Results: For the total 36-hour period, results were as follows: average time of CGM readings in range 70-250 mg/dl: 88.6%, in range 70-180 mg/dl: 74.7%, <70 mg/dl: 5.8%, and <50 mg/dl: 0.8%. Results improved analyzing the final 15-hour period of this trial. In that case, the time spent in range was 70-250 mg/dl: 94.7%, in range 70-180 mg/dl: 82.6%, <70 mg/dl: 4.1%, and <50 mg/dl: 0.2%. During the last night the time spent in range was 70-250 mg/dl: 95%, in range 70-180 mg/dl: 87.7%, <70 mg/dl: 5.0%, and <50 mg/dl: 0.0%. No severe hypoglycemia occurred. No serious adverse events were reported.

Conclusions: The ARG algorithm was successfully validated in a pilot clinical trial, encouraging further tests with a larger number of patients and in outpatient settings.
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http://dx.doi.org/10.1177/1932296818786488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134619PMC
September 2018

18th International Congress on Infectious Diseases/XVIII Congreso SADI 2018-It takes two to Tango.

Int J Infect Dis 2018 08 22;73S:1-2. Epub 2018 Jun 22.

International Society for Infectious Diseases, Brookline, MA, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ijid.2018.06.015DOI Listing
August 2018

Clinical and genetic factors influencing acenocoumarol dosing: a cross-sectional study.

Blood Coagul Fibrinolysis 2018 Sep;29(6):496-500

Clinical Pharmacology Section, Internal Medicine Department.

: Coumadin oral anticoagulants are widely used in multiple clinical scenarios. Their narrow therapeutic range and a dosing strategy based on 'a posteriori' algorithms, pose them as an interesting group for prediction modelling research. Extensive literature explaining the association between clinical and genetic variables with the dose of warfarin have been published. Limited information exists regarding these factors and acenocoumarol dosing. The aim of the study is to explain through clinical/genetic variables, the weekly dose of acenocoumarol necessary for achieving stable anticoagulation status. We performed a cross-sectional study enrolling adults under treatment with acenocoumarol with at least three consecutive INRs between 2 and 3. To explain the association between demographic, clinical and genotype data (VKORC1, CYP2C9 and CYP4F2) and the mean weekly dose of acenocoumarol, we performed a multiple linear regression model. In our cohort, a higher age, the presence of atrial fibrillation, chronic renal failure and VKORC1 haplotype A were associated with a lower mean weekly dose of acenocoumarol. On the other side, a higher weight was associated with a higher weekly dose. Amongst anticoagulated adult patients, VKORC1 genotype and baseline clinical factors can explain acenocoumarol dosing, and therefore, help clinicians while deciding the initial anticoagulant dose.
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http://dx.doi.org/10.1097/MBC.0000000000000746DOI Listing
September 2018

Prediction of severe toxicity in adult patients under treatment with 5-fluorouracil: a prospective cohort study.

Anticancer Drugs 2017 10;28(9):1039-1046

aClinical Pharmacology Section bClinical Oncology Section, Internal Medicine Department cInternal Medicine Section, Internal Medicine Department dMolecular Biology Section, Central Laboratory, Hospital Italiano de Buenos Aires ePharmacology Department, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina.

5-Fluorouracil (5-FU) has long been used for the treatment of gastrointestinal tumors harboring interindividual variability in both the pharmacokinetic and the pharmacogenetic profiles, which in turn may lead to life-threatening toxicities. We carried out a prospective cohort study of adult patients initiating treatment with 5-FU between 2013 and 2015. Primary exposures of interest were the methylenetetrahydrofolate reductase single nucleotide polymorphism in exons 4 and 7 and 5'-untranslated region-thymidylate synthase VNTR genotypes, in addition to baseline clinical and demographic variables. The primary outcome was the time to the occurrence of severe toxicity. We used a Cox regression model to evaluate patients' survival and toxicity experience and its association with baseline characteristics and a priori determined genetic polymorphisms. A total of 197 patients were included, 40.1% developed severe toxicity during follow-up. Variables that were significantly associated with developing severe toxicity were the European Organization for Research and Treatment of Cancer functional score [hazard ratio (HR): 0.98; 95% confidence interval (CI): 0.97-0.99]; type of tumor [anus (HR: 2.50; 95% CI: 1.07-5.82), head and neck/esophagus/stomach (HR: 2.95; 95% CI: 1.64-5.33)] and 5-FU continuous infusion regimens over 4-5 days (HR: 9.35; 95% CI: 2.68-32.59). We found a significant association between baseline functional status, type of tumor and continuous infusion regimens and the occurrence of severe toxicity during the follow-up of patients receiving 5-FU. No association was found with the genotypic variants evaluated. Future validation and modeling of an everyday easy-to-use score to predict toxicity among these subgroup of patients remains warranted.
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http://dx.doi.org/10.1097/CAD.0000000000000546DOI Listing
October 2017

Body composition and metabolic outcomes after 96 weeks of treatment with ritonavir-boosted lopinavir plus either nucleoside or nucleotide reverse transcriptase inhibitors or raltegravir in patients with HIV with virological failure of a standard first-line antiretroviral therapy regimen: a substudy of the randomised, open-label, non-inferiority SECOND-LINE study.

Lancet HIV 2017 01 1;4(1):e13-e20. Epub 2016 Nov 1.

The Kirby Institute, University of New South Wales, Sydney, NSW, Australia.

Background: Lipoatrophy is one of the most feared complications associated with the use of nucleoside or nucleotide reverse transcriptase inhibitors (N[t]RTIs). We aimed to assess soft-tissue changes in participants with HIV who had virological failure of a first-line antiretroviral (ART) regimen containing a non-nucleoside reverse transcriptase inhibitor plus two N(t)RTIs and were randomly assigned to receive a second-line regimen containing a boosted protease inhibitor given with either N(t)RTIs or raltegravir.

Methods: Of the 37 sites that participated in the randomised, open-label, non-inferiority SECOND-LINE study, eight sites from five countries (Argentina, India, Malaysia, South Africa, and Thailand) participated in the body composition substudy. All sites had a dual energy x-ray absorptiometry (DXA) scanner and all participants enrolled in SECOND-LINE were eligible for inclusion in the substudy. Participants were randomly assigned (1:1), via a computer-generated allocation schedule, to receive either ritonavir-boosted lopinavir plus raltegravir (raltegravir group) or ritonavir-boosted lopinavir plus two or three N(t)RTIs (N[t]RTI group). Randomisation was stratified by site and screening HIV-1 RNA. Participants and investigators were not masked to group assignment, but allocation was concealed until after interventions were assigned. DXA scans were done at weeks 0, 48, and 96. The primary endpoint was mean percentage and absolute change in peripheral limb fat from baseline to week 96. We did intention-to-treat analyses of available data. This substudy is registered with ClinicalTrials.gov, number NCT01513122.

Findings: Between Aug 1, 2010, and July 10, 2011, we recruited 211 participants into the substudy. The intention-to-treat population comprised 102 participants in the N(t)RTI group and 108 participants in the raltegravir group, of whom 91 and 105 participants, respectively, reached 96 weeks. Mean percentage change in limb fat from baseline to week 96 was 16·8% (SD 32·6) in the N(t)RTI group and 28·0% (37·6) in the raltegravir group (mean difference 10·2%, 95% CI 0·1-20·4; p=0·048). Mean absolute change was 1·04 kg (SD 2·29) in the N(t)RTI group and 1·81 kg (2·50) in the raltegravir group (mean difference 0·6, 95% CI -0·1 to 1·3; p=0·10).

Interpretation: Our findings suggest that for people with virological failure of a first-line regimen containing efavirenz plus tenofovir and lamivudine or emtricitabine, the WHO-recommended switch to a ritonavir-boosted protease inhibitor plus zidovudine (a thymidine analogue nucleoside reverse transcriptase inhibitor) and lamivudine might come at the cost of peripheral lipoatrophy. Further study could help to define specific groups of people who might benefit from a switch to an N(t)RTI-sparing second-line ART regimen.

Funding: The Kirby Institute and the Australian National Health and Medical Research Council.
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http://dx.doi.org/10.1016/S2352-3018(16)30189-8DOI Listing
January 2017

Tramadol Induced QTc-Interval Prolongation: Prevalence, Clinical Factors and Correlation to Plasma Concentrations.

Curr Drug Saf 2016 ;11(3):206-14

Department of Pharmacology, School of Medicine, University of Buenos Aires, Paraguay 2155 - Piso 16, C1121ABG Ciudad Autónoma de Buenos Aires, Argentina.

Unlabelled: In recent years, several cases of torsade de pointes have been associated with many opioids. However, to present no cases have been reported with tramadol.

Objective: To evaluate the effect of tramadol on QT-interval in the clinical setting.

Research Design And Methods: Medical history and comorbidities predisposing to QT interval prolongation were registered for patients requiring medical assistance that involved tramadol administration. Ionograms and ECGs were performed at baseline and intratreatment; QT interval was analyzed after correction with Bazzet, Fridericia, Framinghan and Hogdes formula.

Results: 115 patients were studied (50.4% males) All patients had received tramadol 150-400 mg/day during 3.0-5.0 days at the moment of intratreatment control. Plasma concentrations of tramadol were 201-1613 ng/mL. Intratreatment electrocardiographic control, as mean ± SD (range), showed QTcB 372±32 (305 to 433), QTcFri 356±37 (281 to 429), QTcFra 363±33 (299 to 429), QTcH 362±30 (304 to 427), ΔQTcB 26±40 (-73 to 110), ΔQTcFri 24±48 (-97 to 121), ΔQTcFra 22±42 (-81 to 109) and .QTcH 22±38 (-68 to 110) ms. QTc interval presents high correlation with plasma tramadol concentrations (for .QTc, R>0.77). Renal failure was associated with a relative risk for ΔQTc > 30 ms of 1.90 (IC95% 1.31-2.74) and for ΔQTc > 60 ms of 4.74 (IC95% 2.57-8.74). No patient had evidence of arrhythmia during the present study.

Conclusion: Tramadol produces QTc interval prolongation in good correlation with plasma drug concentrations; renal failure is a risk factor for higher concentration and QT prolongation by tramadol.
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http://dx.doi.org/10.2174/1574886311666160225150405DOI Listing
February 2017

Which HIV patients should be screened for osteoporosis: an international perspective.

Curr Opin HIV AIDS 2016 May;11(3):268-76

aHIV Molecular Research Group, School of Medicine, University College Dublin, Dublin, Ireland bInfectious Diseases and Clinical Pharmacology Sections, Internal Medicine Service, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina cThe Kirby Institute for Infection and Immunity in Society, University of New South Wales, Sydney, Australia dSchool of Medicine, Hacettepe University, Ankara, Turkey eDepartment of Infectious Diseases at Peking Union Medical College Hospital, Beijing, China fInfectious Diseases Institute (IDI) HIV outpatient clinic at Mulago Hospital Complex, Makerere University College of Health Sciences, Kampala, Uganda gMoscow Regional AIDS Centre, Moscow, Russia hInfectious Diseases Unit Hospital Clinic - Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain iICH Study Center, Hamburg, Germany jToronto General Research Institute (TGRI), University Health Network (NHN), Toronto General Hospital, Toronto, Canada kDivision of Endocrinology, Diabetes & Metabolism, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA lMater Misericordiae University Hospital, Department of Infectious Diseases, Dublin, Ireland.

Purpose Of Review: This review provides international insights into the real-world clinical approach to screening for bone mineral density (BMD) and osteoporosis in people living with HIV (PLWH) using opinions from HIV physicians from key regions around the world.

Recent Findings: Although a significant proportion of PLWH are aged over 50, the relative importance of low BMD to clinical care differs significantly between countries and regions, based on factors such as the population at risk, access to adequate screening resources, and physicians' knowledge. Generally, management of osteoporosis in PLWH follows similar principals as for the general population, with risk factors for fracture combined with measurement of BMD by dual energy X-ray absorptiometry in algorithms such as Fracture Risk Assessment Tool, designed to provide an overall risk estimation. Although in most regions age is considered among the most important factors contributing to low BMD and fractures, considerable country and region-specific factors become apparent, such as malnutrition, inactivity and impact of comorbidities, substance abuse, and increasing use of tenofovir disoproxil fumarate.

Summary: These opinions highlight the diversity that still exists in the approach to the long-term management of PLWH and highlight challenges facing development of consensus guidelines that can be effectively implemented worldwide.
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http://dx.doi.org/10.1097/COH.0000000000000269DOI Listing
May 2016

Water, electrolytes, and acid-base alterations in human immunodeficiency virus infected patients.

World J Nephrol 2016 Jan;5(1):33-42

Carlos G Musso, Division of Nephrology, Department of Medicine, Hospital Italiano de Buenos Aires, Buenos Aires C1199ABB, Argentina.

The clinical spectrum of human immunodeficiency virus (HIV) infection associated disease has changed significantly over the past decade, mainly due to the wide availability and improvement of combination antiretroviral therapy regiments. Serious complications associated with profound immunodeficiency are nowadays fortunately rare in patients with adequate access to care and treatment. However, HIV infected patients, and particularly those with acquired immune deficiency syndrome, are predisposed to a host of different water, electrolyte, and acid-base disorders (sometimes with opposite characteristics), since they have a modified renal physiology (reduced free water clearance, and relatively increased fractional excretion of calcium and magnesium) and they are also exposed to infectious, inflammatory, endocrinological, oncological variables which promote clinical conditions (such as fever, tachypnea, vomiting, diarrhea, polyuria, and delirium), and may require a variety of medical interventions (antiviral medication, antibiotics, antineoplastic agents), whose combination predispose them to undermine their homeostatic capability. As many of these disturbances may remain clinically silent until reaching an advanced condition, high awareness is advisable, particularly in patients with late diagnosis, concomitant inflammatory conditions and opportunistic diseases. These disorders contribute to both morbidity and mortality in HIV infected patients.
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http://dx.doi.org/10.5527/wjn.v5.i1.33DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707166PMC
January 2016

Drug-Induced QTc Interval Prolongation: A Multicenter Study to Detect Drugs and Clinical Factors Involved in Every Day Practice.

Curr Drug Saf 2016 ;11(1):86-98

University of Buenos Aires, Argentina.

Objective: The actual prevalence of drug induced QTc prolongation in clinical practice is unknown. Our objective was to determine the occurrence and characteristics of drug-induced QT prolongation in several common clinical practices. Additionally, a subgroup of patients treated with dextropropoxyphene of particular interest for the regulatory authority was analysed.

Research Design And Methods: Medical history and comorbidities predisposing to QT interval prolongation were registered for 1270 patient requiring medical assistance that involved drug administration. Three ionograms and ECGs were performed: baseline, intra- and after treatment; QT interval was corrected with Bazzet formula.

Results: Among patients, 9.9% presented QTc >450/470 ms, 3% QTc > 500 ms, 12.7% ΔQTc >30 ms and 5.2% ΔQTc >60 ms. QTc prolongation associated with congestive heart failure, ischemic cardiopathy, diabetes, renal failure, arrhythmias, hypothyroidism, and bradycardia. At univariate analysis, clarithromycin, haloperidol, tramadol, amiodarone, glyceryl trinitrate, amoxicillin + clavulanic acid, amoxicillin + sulbactam, ampicillin + sulbactam, fentanyl, piperacillin + tazobactam, and diazepam prolonged QTc. Prolongation remained significantly associated with furosemide, clarithromycin, glyceryl trinitrate and betalactamase inhibitors after multivariate analysis.

Conclusion: QT interval prolongation in everyday practice is frequent, in association to clinical factors and drugs that can be easily identified for monitoring and prevention strategies.
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http://dx.doi.org/10.2174/1574886311207040262DOI Listing
December 2016

Impact of renal aging on drug therapy.

Postgrad Med 2015 Aug 9;127(6):623-9. Epub 2015 Jul 9.

Nephrology Division, Hospital Italiano de Buenos Aires , Buenos Aires , Argentina.

Elderly patients (age ≥ 65 years old) use up to 30% of all commonly prescribed medication, and they suffer more their adverse effects than the general population. In order to minimize this risk, physicians should avoid polypharmacy, dangerous pharmacological interactions and take into account pharmacodynamic and senile pharmacokinetic changes before prescribing any medication to the elderly. The present review article originally describes how renal physiology changes secondary to aging such as dysautonomia, glomerular filtration rate reduction, tubular back-filtration, sodium, calcium and magnesium loss, potassium retention, altered dilution-concentration capability, tubular frailty, genetics, internal milieu and body composition are senile changes that when combined predispose elderly people to suffer from pharmacological adverse effects. Knowledge of these physiological modifications associated with aging and their impact on the pharmacology of particular drugs may help to optimize drug use and to avoid complications in this age group.
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http://dx.doi.org/10.1080/00325481.2015.1063957DOI Listing
August 2015

INVESTIGATING THE EFFICACY OF CLINICAL TRIAL MONITORING STRATEGIES: Design and Implementation of the Cluster Randomized START Monitoring Substudy.

Ther Innov Regul Sci 2015 Mar;49(2):225-233

CICAL and Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.

Background: Trial monitoring protects participant safety and study integrity. While monitors commonly go on-site to verify source data, there is little evidence that this practice is efficient or effective. An ongoing international HIV treatment trial (START) provides an opportunity to explore the usefulness of different monitoring approaches.

Methods: All START sites are centrally monitored and required to follow a local monitoring plan requiring specific quality assurance activities. Additionally, sites were randomized (1:1) to receive, or not receive, annual on-site monitoring. The study will determine if on-site monitoring increases the identification of major protocol deviations (eligibility or consent violations, improper study drug use, primary or serious event underreporting, data alteration or fraud).

Results: The START study completed enrollment in December 2013, with planned follow-up through December 2016. The monitoring study is ongoing at 196 sites in 34 countries. Results are expected when the START study concludes in December 2016.
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http://dx.doi.org/10.1177/2168479014555912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4426264PMC
March 2015

Clinical outcomes of first-line antiretroviral therapy in Latin America: analysis from the LATINA retrospective cohort study.

Int J STD AIDS 2016 Feb 3;27(2):118-26. Epub 2015 Mar 3.

CICAL, Buenos Aires, Argentina Hospital José M. Ramos Mejía, Buenos Aires, Argentina.

Nearly 2 million people are infected with human immunodeficiency virus (HIV) in Latin America. However, information regarding population-scale outcomes from a regional perspective is scarce. We aimed to describe the baseline characteristics and therapeutic outcomes of newly-treated individuals with HIV infection in Latin America. A Retrospective cohort study was undertaken. The primary explanatory variable was combination antiretroviral therapy based on either a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI). The main outcome was defined as the composite of all-cause mortality and the occurrence of an AIDS-defining clinical event or a serious non-AIDS-defining event during the first year of therapy. The secondary outcomes included the time to a change in treatment strategy. All analyses were performed according to the intention to treat principle. A total of 937 treatment-naive patients from four participating countries were included (228 patients with PI therapy and 709 with NNRTI-based treatment). At the time of treatment initiation, the patients had a mean age of 37 (SD: 10) years and a median CD4 + T-cell count of 133 cells/mm(3) (interquartile range: 47.5-216.0). Patients receiving PI-based regimens had a significantly lower CD4 + count, a higher AIDS prevalence at baseline and a shorter time from HIV diagnosis until the initiation of treatment. There was no difference in the hazard ratio for the primary outcome between groups. The only covariates associated with the latter were CD4 + cell count at baseline, study site and age. The estimated hazard ratio for the time to a change in treatment (NNRTI vs PI) was 0.61 (95% CI 0.47-0.80, p < 0.01). This study concluded that patients living with HIV in Latin America present with similar clinical outcomes regardless of the choice of initial therapy. Patients treated with PIs are more likely to require a treatment change during the first year of follow up.
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http://dx.doi.org/10.1177/0956462415575621DOI Listing
February 2016

Bone mineral density over 96 weeks in adults failing first-line therapy randomized to raltegravir/lopinavir/ritonavir compared with standard second-line therapy.

J Acquir Immune Defic Syndr 2014 Oct;67(2):161-8

*The Kirby Institute, University of New South Wales, Sydney, Australia; †UCD School of Medicine and Medical Science, Dublin, Ireland; ‡The Alfred Hospital, Melbourne, Australia; §Thai Red Cross AIDS Research Center, Bangkok, Thailand; ‖Hopital Saint-Louis, Paris, France; and ¶CICAL, Buenos Aires, Argentina.

Objective: To compare bone mineral density (BMD) changes over 96 weeks in adults virologically failing standard first-line therapy, randomized to raltegravir plus lopinavir/ritonavir (RAL + LPV/r) or conventional 2-3 nucleoside/nucleotide reverse transcriptase inhibitors [N(t)RTIs] + LPV/r second-line therapy.

Methods: Participants underwent dual-energy x-ray absorptiometry at baseline and weeks 48 and 96 to measure total hip and lumbar spine BMD. Analyses were adjusted for gender, body mass index, and smoking. Linear regression was used to compare between-group differences, logistic regression for low BMD (hip or spine Z-score ≤ -2) incidence, and multivariate linear regression to determine predictors of BMD change. This work represents the extension and final results of the previously published initial 48 weeks of the study.

Results: The population included 210 adults from 5 middle-income countries: 52% females, 52% Asians, 43% Africans, mean age, 39 years (SD, 8 years). In the 2-3 N(t)RTI group (vs. RAL), BMD reduction was greater at the spine (mean change, -4.9% vs. -3.5%; adjusted difference, -1.9%; 95% confidence interval: -3.3 to -0.5%, P = 0.009) and hip (-4.1% vs. -2.2%; -1.9%; -3.4 to -0.4; P = 0.012). BMD decrease was greatest at 48 weeks with stabilization to week 96. Overall, low BMD occurred in 15 participants (7.9%), with no between-group differences. Independent predictors for bone loss included lower body mass index (regression coefficient: hip, -0.18% and spine, -0.26% per 1 kg/m), longer tenofovir exposure (hip, -0.74% and spine, -1.0% per year), greater change in CD4 to week 12 (hip, -5.11% per 10-fold higher), and higher baseline HIV-RNA (spine, -0.7% per 10-fold higher).

Conclusions: Over 96 weeks, there was greater BMD decrease with 2-3 N(t)RTI + LPV/r compared with RAL + LPV/r; the relative decrease at the spine was greater than the hip. BMD decreases with second-line antiretroviral therapy largely occurred in the first 48 weeks with stabilization, but no recovery thereafter.
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http://dx.doi.org/10.1097/QAI.0000000000000288DOI Listing
October 2014

Impaired Urine Dilution Capability in HIV Stable Patients.

Int J Nephrol 2014 31;2014:381985. Epub 2014 Mar 31.

Renal Physiology Section, Nephrology Service, Hospital Italiano de Buenos Aires, Peron 4190, 1181 ACH Buenos Aires, Argentina.

Renal disease is a well-recognized complication among patients with HIV infection. Viral infection itself and the use of some antiretroviral drugs contribute to this condition. The thick ascending limb of Henle's loop (TALH) is the tubule segment where free water clearance is generated, determining along with glomerular filtration rate the kidney's ability to dilute urine. Objective. We analyzed the function of the proximal tubule and TALH in patients with HIV infection receiving or not tenofovir-containing antiretroviral treatment in comparison with healthy seronegative controls, by applying a tubular physiological test, hyposaline infusion test (Chaimowitz' test). Material & Methods. Chaimowitz' test was performed on 20 HIV positive volunteers who had normal renal functional parameters. The control group included 10 healthy volunteers. Results. After the test, both HIV groups had a significant reduction of serum sodium and osmolarity compared with the control group. Free water clearance was lower and urine osmolarity was higher in both HIV+ groups. Proximal tubular function was normal in both studied groups. Conclusion. The present study documented that proximal tubule sodium reabsorption was preserved while free water clearance and maximal urine dilution capability were reduced in stable HIV patients treated or not with tenofovir.
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http://dx.doi.org/10.1155/2014/381985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3988737PMC
May 2014

[Cardiovascular pharmacogenomics].

Arch Cardiol Mex 2014 Jan-Mar;84(1):25-31. Epub 2014 Mar 11.

Sección de Farmacología Clínica, Servicio de Clínica Médica, Departamento de Medicina, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina; Cátedra de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.

Cardiovascular disease remains a major cause of morbidity and mortality worldwide. Current medical practice takes into account information based on population studies and benefits observed in large populations or cohorts. However, individual patients present great differences in both toxicity and clinical efficacy that can be explained by variations in adherence, unknown drug to drug interactions and genetic variability. The latter seems to explain from 20% up to 95% of patient to patient variability. Treating patients with cardiovascular disorders faces the clinician with the challenge to include genomic analysis into daily practice. There are several examples within cardiovascular disease of treatments that can vary in toxicity or clinical usefulness based on genetic changes. One of the main factors affecting the efficacy of Clopidogrel is the phenotype associated with polymorphisms in the gene CYP 2C9. Furthermore, regarding oral anticoagulants, changes in CYP2C9 and VKORC1 play an important role in changing the clinical response to anticoagulation. When analyzing statin treatment, one of their main toxicities (myopathy) can be predicted by the SLCO1B1 polymorphism. The potential for prediction of toxicity and clinical efficacy from the use of genetic analysis warrants further studies aiming towards its inclusion in daily clinical practice.
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http://dx.doi.org/10.1016/j.acmx.2013.11.003DOI Listing
January 2015

HIV lipodystrophy in participants randomised to lopinavir/ritonavir (LPV/r) +2-3 nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTI) or LPV/r + raltegravir as second-line antiretroviral therapy.

PLoS One 2013 30;8(10):e77138. Epub 2013 Oct 30.

The Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia.

Objective: To compare changes over 48 weeks in body fat, lipids, Metabolic Syndrome and cardiovascular disease risk between patients randomised 1:1 to lopinavir/ritonavir (r/LPV) plus raltegravir (RAL) compared to r/LPV plus 2-3 nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs) as second-line therapy.

Methods: Participants were HIV-1 positive (>16 years) failing first-line treatment (2 consecutive HIV RNA >500 copies/mL) of NNRTI +2N(t)RTI. Whole body dual energy x-ray absorptiometry was performed at baseline and week 48. Data were obtained to calculate the Metabolic Syndrome and Framingham cardiovascular disease (CVD) risk score. Linear regression was used to compare mean differences between arms. Logistic regression compared incidence of metabolic syndrome. Associations between percent limb fat changes at 48 weeks with baseline variables were assessed by backward stepwise multivariate linear regression. Analyses were adjusted for gender, body mass index and smoking status.

Results: 210 participants were randomised. The mean (95% CI) increase in limb fat over 48 weeks was 15.7% (5.3, 25.9) or 0.9 kg (0.2, 1.5) in the r/LPV+N(t)RTI arm and 21.1% (11.1, 31,1) or 1.3 kg (0.7, 1.9) in the r/LPV+RAL arm, with no significant difference between treatment arms (-5.4% [-0.4 kg], p>0.1). Increases in total body fat mass (kg) and trunk fat mass (kg) were also similar between groups. Total:HDL cholesterol ratio was significantly higher in the RAL arm (mean difference -0.4 (1.4); p = 0.03), there were no other differences in lipid parameters between treatment arms. There were no statistically significant differences in CVD risk or incidence of Metabolic Syndrome between the two treatment arms. The baseline predictors of increased limb fat were high viral load, high insulin and participant's not taking lipid lowering treatment.

Conclusion: In patients switching to second line therapy, r/LPV combined with RAL demonstrated similar improvements in limb fat as an N(t)RTI + r/LPV regimen, but a worse total:HDL cholesterol ratio over 48 weeks.

Trial Registration: This clinical trial is registered on Clinicaltrials.gov, registry number NCT00931463 http://clinicaltrials.gov/ ct2/show/NCT00931463?term = NCT00931463&rank = 1.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0077138PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3813715PMC
August 2014

Contribution of genetic background, traditional risk factors, and HIV-related factors to coronary artery disease events in HIV-positive persons.

Clin Infect Dis 2013 Jul 26;57(1):112-21. Epub 2013 Mar 26.

Institute of Microbiology, University Hospital Center, University of Lausanne, Lausanne, Switzerland.

Background: Persons infected with human immunodeficiency virus (HIV) have increased rates of coronary artery disease (CAD). The relative contribution of genetic background, HIV-related factors, antiretroviral medications, and traditional risk factors to CAD has not been fully evaluated in the setting of HIV infection.

Methods: In the general population, 23 common single-nucleotide polymorphisms (SNPs) were shown to be associated with CAD through genome-wide association analysis. Using the Metabochip, we genotyped 1875 HIV-positive, white individuals enrolled in 24 HIV observational studies, including 571 participants with a first CAD event during the 9-year study period and 1304 controls matched on sex and cohort.

Results: A genetic risk score built from 23 CAD-associated SNPs contributed significantly to CAD (P = 2.9 × 10(-4)). In the final multivariable model, participants with an unfavorable genetic background (top genetic score quartile) had a CAD odds ratio (OR) of 1.47 (95% confidence interval [CI], 1.05-2.04). This effect was similar to hypertension (OR = 1.36; 95% CI, 1.06-1.73), hypercholesterolemia (OR = 1.51; 95% CI, 1.16-1.96), diabetes (OR = 1.66; 95% CI, 1.10-2.49), ≥ 1 year lopinavir exposure (OR = 1.36; 95% CI, 1.06-1.73), and current abacavir treatment (OR = 1.56; 95% CI, 1.17-2.07). The effect of the genetic risk score was additive to the effect of nongenetic CAD risk factors, and did not change after adjustment for family history of CAD.

Conclusions: In the setting of HIV infection, the effect of an unfavorable genetic background was similar to traditional CAD risk factors and certain adverse antiretroviral exposures. Genetic testing may provide prognostic information complementary to family history of CAD.
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http://dx.doi.org/10.1093/cid/cit196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3669528PMC
July 2013

[Pharmacogenomics in gastroenterologic diseases].

Acta Gastroenterol Latinoam 2012 Mar;42(1):64-72

Unidad de Medicina Molecular y Genómica del Instituto de Ciencias Básicas y Medicina Experimental, Escuela de Medicina del Hospital Italiano de Buenos Aires, Argentina.

Pharmacogenomics is the study of genetic variations that produce a modification of the response to drugs. These variations are expressed as a different capacity for the metabolism or the transport of drugs, or a variable activity of drug receptors. Drug use in gastroenterology offers different examples of the use of pharmacogenomic analysis in the identification of the appropriate drug and drug dose for each individual patient. The use of proton pump inhibitors in the treatment of gastroesophagic reflux disease and Helicobacter pylori eradication may be optimized by the analysis of polymorphisms of the CYP2C19 gene. Additionally, the study of variants of IL28 helps in the identification of patients with more chances of response to the treatment of hepatitis C with interferon and ribavirin. The analysis of polymorphisms of the gene coding for the enzyme thiopurine methyl transferase (TPMT) helps in the reduction of the risks associated with the use of azathioprine in the treatment of inflammatory bowel disease. In this way, pharmacogenomics constitute not only a therapeutic tool that already shows an impact in the individualization of drug use in gastroenterology but also a tool with a great projection in the future.
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March 2012

Recurrent Meningitis and Subarachnoid Hemorrhage Due to Salmonella in an HIV+ Patient: Case Report and Mini-Review of the Literature.

Open AIDS J 2011 11;5:62-6. Epub 2011 Jul 11.

Infectious Diseases Section, Internal Medicine Service, Hospital Italiano de Buenos Aires, Argentina.

Meningitis due to non-typhi salmonella is infrequent in HIV-positive adults.We report a case of a patient with >300 CD4+ cells/mm3 who presented with five episodes of recurrent meningitis, focal subarachnoid hemorrhage and cerebral vasculitis ultimately attributed to Salmonella choleraesuis infection. Even within the cART era invasive salmonellosis can occur in unusual ways in HIV-infected patients.
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http://dx.doi.org/10.2174/1874613601105010062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139252PMC
November 2011

Influence of CYP3A5 polymorphism on tacrolimus maintenance doses and serum levels after renal transplantation: age dependency and pharmacological interaction with steroids.

Pediatr Transplant 2011 Aug 28;15(5):525-32. Epub 2011 Jun 28.

Servicio de Nefrología Pediátrica, Hospital Italiano de Buenos Aires Departamento de Pediatría, Universidad de Buenos Aires.

  TAC, MMF and MP are used in pediatric kidney tx. The cytochrome P450 (CYP)3A5 enzyme appears to play a role in TAC metabolism. The aims of this study were to investigate CYP3A5 polymorphism's effect on TAC dosing and the age dependency of TAC dosing by testing blood concentrations, and the interaction between steroids and TAC during the first year after tx. Genomic DNA was extracted and amplified with specific primers. CYP3A5 alleles were confirmed by direct sequencing of PCR products on an automated AB13100 capillary sequencer. We studied 48 renal transplant patients (age at tx 12±0.5yr, 22 boys) receiving TAC, MMF, MP. Of these, 79% were CYP3A5*3/*3 (non-expressers homozygotes) and 21% were CYP3A5*1/*3 (expressers). TAC trough levels were 7.1±0.4ng/mL in CYP3A5*3/*3 patients and 6.5±0.7ng/mL in CYP3A5*1/*3 group (p=0.03). CYP3A5*1/*3 patients had lower levels of dose-adjusted TAC (36.7±5.8ng/mL/mg/kg/day) to achieve target blood concentration and required higher daily dose per weight (0.21±0.03mg/kg/day) than CYP3A5*3/*3 patients, 72.4±8.0ng/mL/mg/kg/day and 0.13±0.01mg/kg/day (p<0.001). Prepubertal patients with different CYP3A5 polymorphisms required significant higher TAC doses and achieved lower dose-normalized concentration compared with pubertal patients. Both TAC dose and adjusted-dose correlated with daily MP dose in CYP3A5*1*3 (r: 0.4, p<0.03 and r: 0.4, p<0.03) and in CYP3A5*3*3 (r: 0.6, p<0.01 and r: 0.47, p<0.001) patients. CYP3A5 polymorphism performed before tx could contribute to a better individualization of TAC therapy. The higher TAC dose in prepubertal patients and the pharmacological interactions between MP and TAC may not be fully explained by different CYP3A5 polymorphisms.
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http://dx.doi.org/10.1111/j.1399-3046.2011.01513.xDOI Listing
August 2011

Development of diagnostic criteria for serious non-AIDS events in HIV clinical trials.

HIV Clin Trials 2010 Jul-Aug;11(4):205-19

Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota 55454-1015, USA.

Purpose: Serious non-AIDS (SNA) diseases are important causes of morbidity and mortality in the HAART era. We describe development of standard criteria for 12 SNA events for Endpoint Review Committee (ERC) use in START, a multicenter international HIV clinical trial.

Methods: SNA definitions were developed based upon the following: (1) criteria from a previous trial (SMART), (2) review of published literature, (3) an iterative consultation and review process with the ERC and other content experts, and (4) evaluation of draft SNA criteria using retrospectively collected reports in another trial (ESPRIT).

Results: Final criteria are presented for acute myocardial infarction, congestive heart failure, coronary artery disease requiring drug treatment, coronary revascularization, decompensated liver disease, deep vein thrombosis, diabetes mellitus, end-stage renal disease, non-AIDS cancer, peripheral arterial disease, pulmonary embolism, and stroke. Of 563 potential SNA events reported in ESPRIT and reviewed by an ERC, 72% met "confirmed" and 13% "probable" criteria. Twenty-eight percent of cases initially reviewed by the ERC required follow-up discussion (adjudication) before a final decision was reached.

Conclusion: HIV clinical trials that include SNA diseases as clinical outcomes should have standardized SNA definitions to optimize event reporting and validation and should have review by an experienced ERC with opportunities for adjudication.
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http://dx.doi.org/10.1310/hct1104-205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109979PMC
December 2010

Changes in inflammatory and coagulation biomarkers: a randomized comparison of immediate versus deferred antiretroviral therapy in patients with HIV infection.

J Acquir Immune Defic Syndr 2011 Jan;56(1):36-43

University of Minnesota, Minneapolis, MN, USA.

Objectives: Among a subgroup of participants in the Strategies for Management of Antiretroviral Therapy (SMART) Trial that were naïve to antiretroviral therapy (ART) or off ART (6 months or longer) at study entry, risk of AIDS and serious non-AIDS events were increased for participants who deferred ART compared with those randomized to (re)initiate ART immediately. Our objective was to determine whether ART initiation in this group reduced markers of inflammation and coagulation that have been associated with increased mortality risk in SMART. Changes in these biomarkers have been described after stopping ART, but not after starting ART in SMART.

Methods: Stored specimens for 254 participants (126 drug conservation [DC] and 128 viral suppression [VS]) who were naïve to ART or off ART (6 months or longer) were analyzed for interleukin-6, high sensitivity C-reactive protein, and D-dimer at baseline and Months 2 and 6.

Results: At Month 6, 62% of the VS group had HIV RNA less than 400 copies/mL and median CD4 count was 190 cells/mm3 higher than for the DC group (590 versus 400 cells/mm3). Compared with DC, the VS group had 32% (95% confidence interval, 19%-43%) lower D-dimer levels at Month 6 (P < 0.001); differences were not significant for high sensitivity C-reactive protein or interleukin-6 levels.

Conclusions: In this randomized comparison of immediate versus delayed ART initiation, D-dimer, but not interleukin-6 and high sensitivity C-reactive protein, declined significantly after starting ART. Further studies are needed to determine whether improvements in D-dimer are associated with reduced risk of clinical disease and whether adjunct treatments used in combination with ART can reduce inflammation among individuals with HIV infection.
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http://dx.doi.org/10.1097/QAI.0b013e3181f7f61aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3005856PMC
January 2011

[Pharmacogenomics and the path towards personalized medicine].

Medicina (B Aires) 2010 ;70(5):482-4

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November 2011

Efavirenz versus boosted atazanavir or zidovudine and abacavir in antiretroviral treatment-naive, HIV-infected subjects: week 48 data from the Altair study.

Clin Infect Dis 2010 Oct;51(7):855-64

National Centre in HIV Epidemiology and Clinical Research, Faculty of Medicine, University of New South Wales, 45 Beach St, Coogee, New South Wales, Australia, 2034.

Background: Antiretroviral therapy is complicated by drug interactions and contraindications. Novel regimens are needed.

Methods: This open label study randomly assigned treatment-naive, human immunodeficiency virus (HIV)-infected subjects to receive tenofovir-emtricitabine with efavirenz (Arm I), with ritonavir-boosted atazanavir (Arm II), or with zidovudine/abacavir (Arm III). Pair-wise comparisons of differences in time-weighted mean change from baseline plasma HIV-RNA to week 48 formed the primary analysis. Treatment arms were noninferior if the upper limit of the 95% confidence interval (CI) was <0.5 log(10) copies/mL. Secondary objectives included virologic, immunologic and safety end points.

Results: The intention-to-treat population comprised 322 patients (Arm I, n = 114; Arm II, n = 105; and Arm III, n = 103). Noninferiority for the primary end point was established. Analysis for superiority showed that Arm III was significantly less potent than Arm I (-0.20 log(10) copies/mL; 95% CI, -0.39 to -0.01 log(10) copies/mL; P = .038). The proportions of patients on each of Arm I (95%) and Arm II (96%) with <200 copies/mL were not different (P = .75), but the percentage of patients in Arm III with <200 copies/mL (82%) was significantly lower (P = .005). CD4+ cell counts did not differ. Serious adverse events were more frequent in Arm III (n = 30) than in Arm I or Arm II (n = 15 for each; P = .062).

Conclusions: A novel quadruple nucleo(t)side combination demonstrated significantly less suppression of HIV replication, compared with the suppression demonstrated by standard antiretroviral therapy regimens, although it did meet the predetermined formal definition of noninferiority. Secondary analyses indicated statistically inferior virologic and safety performance. Efavirenz and ritonavir-boosted atazanavir arms were equivalent in viral suppression and safety.
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http://dx.doi.org/10.1086/656363DOI Listing
October 2010
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